PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is destruction of lung tissue and/or thickening of lung airways. It is the fourth leading cause of death in the USA. COPD is progressive and characterized by chronic inflammation and shortness of breath on exertion, which leads to physical inactivity and skeletal muscle dysfunction. Survival rate in COPD is more closely associated with exercise capacity than the severity of lung disease. A key determinant of exercise capacity is the ability of skeletal muscle mitochondria to sustain cellular energy delivery (termed, oxidative capacity). We recently applied a noninvasive near-infrared light-based method to assess muscle oxidative capacity in 245 smokers with and without COPD: the COPDGene ancillary Muscle Health Study. We showed that severe COPD patients have a 40% lower muscle oxidative capacity than smokers or never smokers with normal lung function. Yet, many questions remain about characteristics and mechanisms behind the loss of muscle oxidative capacity in COPD. The current proposal will follow-up with 200 of the Muscle Health Study participants to determine for the first time the rate of decline in lower limb skeletal muscle oxidative capacity over 5 years. Using the individual genetics, triaxial accelerometer measured daily physical activity, body composition measured by DXA, and 808 other clinical variables collected in the COPDGene parent study, we will identify clinical, behavioral and genetic variables that associate with the 5-year decline in skeletal muscle oxidative capacity. In addition, quadriceps muscle biopsy samples from 20 COPD patients with the fastest decline and 20 with the slowest decline in muscle oxidative capacity, identified by the near-infrared based noninvasive assessment, will be used to discover how gene expression is altered by the disease. DNA methylation and expression of small and large RNAs, including small non-coding RNAs from the mitochondrial genome (mitosRNAs), will be probed. These highly specific approaches will provide a detailed profile of mitochondrial and nuclear genes and/or gene networks underlying the causes of derangements in the lower limb skeletal muscles of COPD patients. The decline in muscle oxidative capacity impairs exercise tolerance and predisposes patients to chronic diseases such as cardiovascular disease, diabetes and obesity, each of which increases risk of premature death. The current proposal will be the first to determine how loss of muscle oxidative capacity progresses in COPD, and answer fundamental questions about the nature of the associations among mitochondrial dysfunction, sedentary lifestyle and poor outcomes in COPD patients. Our findings will guide efforts to create new therapeutic strategies to prevent skeletal muscle dysfunction, increase autonomy, hospital free survival and quality-of-life in COPD.